This program uses human bone marrow transplantation and basic laboratory studies to investigate the mechanism of graft-versus-leukemia effect and graft-versus-host disease in humans and engineering of the bone marrow graft to improve the clinical outcome of transplantation. Analysis of results from about 50 patients who have undergone bone marrow transplantation in our Clinical Center unit has indicated the importance of an adequate dose of stem cells and sufficient lymphocyte depletion to assure engraftment and a low rate of graft-versus-host disease, respectively. These data have led to development of a novel protocol which employs T lymphocyte-depleted and hematopoietic growth factor-mobilized peripheral blood stem cells as the stem cell source in the transplant. To date, large stem cells doses have been delivered leading to very rapid recovery of blood counts. As with bone marrow transplants, lymphocytes are added later to restore immune system function. Replacement of bone marrow by peripheral blood appears to reduce the frequency of graft-versus-host disease and other transplant-related complications. To enhance graft-versus-leukemia effects, a technique has been developed for generating leukemia-specific T cells using peptides derived from a marrow cell protein (proteinase 3). Cells with this specificity will be used to treat patients who relapse with leukemia after transplantation. Other laboratory studies aim at identification of antigens that are unique or prevalent on leukemia and tumor cells in order to stimulate donor T lymphocyte responses in vitro prior to transplantation or a malignant diseases.